Many of the mechanisms for regulation of leukemic and normal hematopoietic differentiation remain to be elucidated. Pluripotent hematopoietic stem cells (HSC) proliferate and give rise to the circulating cells of the hematopoietic system. When malignancy occurs, leukemic cells take over the differentiative compartments of the bone marrow and eventually the leukemic process results in death. The presence of a functional thymus has been shown to be important for the resistance of RNA oncogenic viruses. We and others have evidence that the cells present in the thymus may interact with HSC to proliferate and differentiate into normal mature elements of the blood. Utilizing several experimental models of defective marrow proliferation, we intend to further explore the functional role of the thymus in the leukemic and normal differentiation of HSC. We are currently studying the mechanism(s) underlying resistance to Friend Leukemia and attempting to induce susceptibility by radiation or mitogen exposure. Development of methods in the model examined here might have broad application, useful for treatment of leukemia.